Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance. Sotatercept, an activin-signaling inhibitor, is a novel therapy targeting this pathology. We conducted a systematic review and meta-analysis to assess its efficacy and safety in PAH. A systematic search of PubMed, Cochrane CENTRAL, Scopus, and Web of Science was conducted, to identify randomized controlled trials (RCTs) evaluating Sotatercept in adults with PAH. Data were pooled using random-effects models to estimate mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs). Four RCTs enrolling 921 patients were included. Compared with placebo, Sotatercept significantly improved 6-minute walk distance (MD 30.54 m, 95% CI 4.05–57.04, P=0.02), WHO functional class (RR 1.71, 95% CI 1.37–2.15, P<0.00001), multicomponent improvement (RR 2.77, 95% CI 1.45–5.29, P=0.002), pulmonary vascular resistance (MD −197.01 dyn⋅s⋅cm ⁻⁵ , 95% CI −213.16 – −180.86, P<0.00001), and reduced clinical worsening events (RR 0.28, 95% CI 0.21–0.38, P<0.00001). There were no significant differences in NT-proBNP levels or all-cause mortality. Safety analysis showed lower risks of serious adverse events (AEs), peripheral edema, and right ventricular failure, but higher rates of bleeding, epistaxis, and drug-related AEs. Sotatercept demonstrated meaningful clinical benefits in exercise capacity, hemodynamics, and disease progression among patients with PAH, with a generally acceptable safety profile. These findings support Sotatercept as a promising adjunct to standard therapy, though longer-term trials are needed to confirm durability and survival impact.

This narrative review synthesizes the available evidence on pregnancy-associated heart failure with preserved ejection fraction (HFpEF) and presents an operational definition and hypothesis-generating conceptual framework for this underrecognized cardio-obstetric phenotype that extends the traditional reduced-ejection-fraction framework of pregnancy-associated heart failure. Pregnancy-associated HFpEF refers to heart failure occurring during pregnancy or postpartum in patients with preserved left ventricular ejection fraction and objective evidence of congestion, elevated cardiac filling pressures, or impaired diastolic function, after consideration of alternative causes. Although peripartum cardiomyopathy has historically shaped the understanding of pregnancy-associated heart failure, limited observational studies and case reports have described heart-failure presentations during pregnancy or postpartum despite preserved left ventricular systolic function. Whether these presentations represent a distinct pregnancy-associated HFpEF phenotype after exclusion of alternative causes remains uncertain. This phenotype is closely linked to hypertensive disorders of pregnancy, obesity, diabetes, renal dysfunction, advanced maternal age, and social vulnerability, and may overlap mechanistically with preeclampsia through shared pathways of endothelial dysfunction, increased afterload, elevated filling pressures, and pulmonary congestion. Diagnosis remains challenging because normal pregnancy can mimic HFpEF symptoms and alter biomarkers and echocardiographic parameters, while existing HFpEF algorithms have not been validated in pregnant populations. Recognition requires integration of clinical evidence of congestion, natriuretic peptide levels, echocardiographic evidence of diastolic dysfunction or elevated filling pressures, assessment of pulmonary hypertension and right ventricular involvement, and the postpartum clinical trajectory. Given the heterogeneity of this phenotype, a personalized-medicine approach may be particularly relevant, integrating maternal risk factors, obstetric context, biomarkers, and cardiac imaging rather than relying on preserved LVEF alone. Although hypertensive disorders of pregnancy are associated with increased long-term cardiovascular and HFpEF risk, whether pregnancy-associated HFpEF itself independently predicts future heart failure remains unknown. The operational definition, conceptual framework, and postpartum considerations presented in this narrative review are intended to organize the available evidence and generate hypotheses rather than serve as a formal diagnostic or management protocol, and they require prospective validation before routine clinical adoption.